This proposal attempts to address the question: is the dysregulation of the Limbic-Hypothalamo-Pituitary-Adrenal (LHPA) Axis observed in depression a result of the stress which either precipitated the depression and/or resulted from it, or does the LHPA axis play a more fundamental role in the biology of depression? If the latter is correct, we would hypothesize that individuals who are prone to depression may respond to psychological stressors differently as monitored by endocrine correlates, and that they may do so not only when in episode, but also when out of episode. It would suggest that information which is laden with negative affect may be remembered differently by depressive individuals, as compared to normal controls. We propose to test these ideas by subjecting depressed patients, in and out of episode, to a social stressor and testing how they respond to it endocrinologically, how rapidly they terminate this response, and how well they habituate to its repeated presentation. We shall also use a newly devised memory test which contrast the ability to remember neutral vs. negative material, and ask whether depressed subjects, be they in or out of episode, show differences from controls in the way they handle emotional material. In addition, we shall test subjects out of episode at the purely neuroendocrine level using some sensitive challenges which we have devised and validated, and which we believe are reflective of the neuronal rather than the peripheral elements of the LHPA axis--these will include a metyrapone test in the evening at the nadir of the rhythm where we observe substantial dysregulation in drive level, and a test of fast feedback in the morning, at the peak of the rhythm, where we have shown a disturbance in glucocorticoid feedback. A complementary approach to addressing this central question is to study a group of subjects undergoing a very stressful life situation ( genetic test for a familial Breast Cancer Gene-BRCA1, to determine whether or not they carry a mutation which gives them an almost 90% chance of developing breast and/or ovarian cancer); evaluating their neuroendocrine profile at that point; and determining whether it resembles that of individuals with major depression. We shall then ask whether an abnormal neuroendocrine profile is correlated with a personal or a family history of major depression, or with the subsequent occurrence of depression or mood disorders, as determined with a 6 month follow-up. Together, this series of studies should shed light on the extent of the relationship between major depression and the dysregulation of stress responsiveness.